The evolution of medical ultrasonics requires continual evaluation of safety issues. Concern presently centers on the nonthermal bioeffects mechanisms of gas body activation (GBA) and inertial cavitation, particularly in relation to the use of gas-body contrast agents in diagnostic ultrasound procedures. If suitable gas bodies are present initially, GBA occurs with a possibility of cell membrane damage. At higher amplitudes, inertial cavitation may be initiated with a risk of cellular DNA damage. In mammals, these phenomena can be subtle or dramatically destructive: the potential exists for both harmful side effects and therapeutic benefit. This research has four specific aims: (1) Sensitive non- rotating exposure systems are planned, which can bring out micro-scale interactions between cells and bubbles and reveal the fundamental dosimetric relationships. (2) Gas-body contrast agents inject the potential for cavitational bioeffects into otherwise risk-free exposure conditions. Experiments will be aimed at characterizing the behavior of these agents at low levels and at determining if they can lead to inertial cavitation under medically-relevant conditions. In addition, the bioeffects capability of the agents will be examined with emphasis on specific targeting of cancer cells for therapeutic purposes. (3) DNA strand breaks induced by direct exposure of cells to inertial cavitation have recently been revealed by the novel "comet" assay. The mechanisms and genetic consequences of such DNA damage will be examined, and its relation, if any to medical ultrasonics will be determined. (4) Intestinal hemorrhage can be induced by either ultrasonic heating or by cavitation acting alone. The possible synergistic enhancement of this effect will be studied when both mechanisms operate. Finally, tissue damage related to cavitation or activation of gas-body contrast agents in other organs, such as the kidney, will be investigated and defined. The quantitative dosimetric information resulting from this research is urgently needed for risk assessment and guidance of sonographers, and for developing the full therapeutic potential of medical ultrasound.